Are Two Drugs Better Than One for PAH?

by Phyllis Hanlon, Contributing Writer  

Research in managing WHO Group 1 PH (PAH, pulmonary arterial hypertension) has resulted in new drugs and strategies that have extended and are improving life for patients. Lately, some doctors have started prescribing more than one drug for patients. Researchers from Brazil and France teamed up to examine how doctors are thinking about multiple-drug therapy for patients with PAH. Their editorial comments were published in the European Respiratory Journal. 

Rogério Souza, M.D., Ph.D., from the Heart Institute at the University of Sao Paulo Medical School, offered some background on the latest in PAH drug therapy. He explained that the current drugs target one of three pathways: the nitric oxide (NO) pathway, the endothelin pathway, and the prostacyclin pathway. He noted that for many years, unless a patient was very sick, doctors initially used one drug (monotherapy). If a patient’s disease continued to get worse, or if the patient and his or her physician did not feel the patient was “responding” to the chosen drug, doctors then frequently added a second drug onto the first – combination therapy. Recent clinical trials began to look closer at combination therapies.

For instance, the AMBITION trial examined the use of both ambrisentan and tadalafil in patients with PAH and found that together they worked better than either drug alone. Summarizing all existing evidence, the European Society of Cardiology (ESC)/European Respiratory Society (ERS) issued guidelines recommending the use of combination therapy, particularly in the early stages of disease.

The editorial added that although existing evidence provides robust support for the use of combination therapy, the RESPITE study took a different approach; instead of combination therapy, this study looked at the effect of switching from PDE5 inhibitors (e.g., sildenafil or tadalafil) to a soluble guanylate cyclase (sGC) stimulator (riociguat) if a patient was not responding adequately to the PDE5 inhibitor.

In the RESPITE study patients were given riociguat after they had been taking sildenafil and tadalafil without any noticeable improvement. All three drugs target the nitric oxide pathway, but in a different manner. The results showed that 84 percent of the patient participants completed the 24-week trial. Patients showed improvements in six-minute walk distance; NT-proBNP, a blood test to look for signs of heart failure; and functional class improvement. Of great importance is the fact that nearly half of the patients in the RESPITE study lowered their risk profile as defined by the ESC/ERS guidelines.

While RESPITE demonstrated good results and raised some important questions, the study did have limitations, according to the authors. They noted that because the study was open-label in design (the researchers knew what drug was being used and there was no placebo involved), it’s difficult to draw any real conclusions. Also, 16 percent of participants failed to complete the entire study; adverse events (“side effects”) might have impacted the final results.

Dr. Souza and co-authors noted that the idea of switching drugs is common in other medical situations, such as treating systemic high blood pressure. But he said that using this approach in PAH faces some different challenges. They asserted that when you look at all the different drugs for PAH in a particular class there is not one that has been proven to be better than the others. Additionally, no study has created a profile of patients with PAH who respond more favorably to one drug over another. Finally, patients with PAH continue to have a relatively high death rate, limiting attempts to test potential switches.

Despite these challenges, several studies on transitioning patients from one drug to another have taken place, to better understand when this would be appropriate and in whom.

While studies have yielded promising results, more questions exist and more clinical trials are needed to answer them. The REPLACE study (Riociguat rEplacing PDE5i therapy evaLuated Against Continued PDE5i thErapy) is currently enrolling participants and is attempting to answer more of these questions.

Each PH patient is different. It is essential that you talk to your own doctor about what treatment options are best for you. For more information on finding a doctor or an accredited care center, visit https://www.phassociation.org/PHCareCenters/Patients.